Abstract
Background/Aims We have previously shown that low birth weight (LBW) rats exposed to intrauterine malnutrition have an impaired lung inflammatory response and reduced levels of inflammatory mediators; however, circulating leptin levels were not increased. We evaluated long leptin receptor isoform (ObRb) expression in lung endothelial cells from low birth weight rats and examined its role in the production of lipid mediators and cytokines. Methods Lung endothelial cells were obtained from normal birth weight (NBW) rats or LBW rats subjected to intrauterine malnutrition. These cells were stimulated with leptin (10 ng/mL), LPS (lipopolysaccharide, 1 μg/mL), or leptin plus LPS. Six hours after stimulation, the production of inflammatory mediators (PGE2, LTB4, IL-1β, and IL-6) was evaluated using commercial ELISA kits, and Western blotting was performed to investigate p38MAPK, NF-κB, and ObRb expression. Results Leptin increased IL-1β levels in only cells from the NBW group, whereas LPS increased PGE2 and LTB4 levels in cells from both groups; leptin addition potentiated lipid mediator production induced by LPS in the NBW group. LPS enhanced the production of IL-1β and IL-6 in only endothelial cells from NBW rats. Leptin receptor expression was decreased (63%) in endothelial cells from LBW rats. None of the stimuli increased NF-κB or p38 signaling pathway expression in cells from LBW rats. Conclusion These results suggest that intrauterine malnutrition compromises leptin receptor expression and cytokine production in pulmonary endothelial cells stimulated by LPS; these effects seem to involve the NF-κB and p38MAPK signaling pathways.
Highlights
Leptin is a nonglycosylated peptide hormone with a molecular weight of 16 kDa; in murine animals, leptin is encoded by the obese gene (Ob), which shows 84% homology with the human leptin gene [1]
We observed that rats with a normal birth weight had increased circulating leptin levels after allergic stimuli in the lung, whereas rats with a low birth weight did not have increased circulating leptin levels or leukotriene production in the lungs after allergic stimulation; these results suggest that leptin plays a role in the reduced inflammatory responses of these animals [13]
Low birth weight rats exposed to intrauterine malnutrition have an impaired lung inflammatory response that is associated with reduced leukotriene B4 (LTB4), leukotriene C4 (LTC4) [11], and interleukin-6 (IL-6) [24] levels in the lung tissue; in addition, circulating leptin levels are not increased
Summary
Leptin (derived from the Greek word “leptos,” meaning thin) is a nonglycosylated peptide hormone with a molecular weight of 16 kDa; in murine animals, leptin is encoded by the obese gene (Ob), which shows 84% homology with the human leptin gene [1]. Primarily synthesized by adipocytes in white adipose tissue, is a pleiotropic molecule involved in promoting energy expenditure and satiety, as well as homeostasis, immunity, and reproductive neuroendocrine and neuroprotective functions [2,3,4]. These effects depend on binding to its receptor, long leptin receptor isoform (ObRb), a transmembrane protein with a cytoplasmic domain that activates signal transduction pathways, Mediators of Inflammation including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein kinase (MAPK) signaling pathways [5, 6]. We observed that rats with a normal birth weight had increased circulating leptin levels after allergic stimuli in the lung, whereas rats with a low birth weight did not have increased circulating leptin levels or leukotriene production in the lungs after allergic stimulation; these results suggest that leptin plays a role in the reduced inflammatory responses of these animals [13]
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